Abstract Asthma is a chronic inflammatory disease of the airways, affecting >25 million Americans. The annual economic cost for asthma exceeds 50 billion dollars, making asthma one of the most common and costly disease. Allergen specific Th2 type CD4 T cell activation and eosinophil infiltration are hallmarks of asthmatic inflammation. Oral or inhaled glucocorticoids have been the frontline treatment to effectively manage asthma for more than 50 years. Yet, the precise mechanisms underlying glucocorticoid-mediated treatment are not well understood. In addition, a cohort of asthmatic patients develops steroid-resistant asthma. Unlike conventional eosinophil-dominant Th2 type inflammation, steroid-resistant asthmatic inflammation is associated with neutrophilic infiltration with effector CD4 T cells displaying Th17 type signature. The current application is built upon unexpected observations that synthetic glucocorticoid, dexamethasone, fails to inhibit eosinophilic airway inflammation in the absence of Foxp3+ Tregs, a CD4 T cell subset that plays a central role in regulating immunity and tolerance. Adoptive Treg transfer into this condition restores dexamethasone treatment effects, supporting the role of Tregs. We also found that neutrophilic airway inflammation model that is dexamethasone resistant is attenuated upon treating with dexamethasone combined with IL-27, a cytokine essential for Treg suppressive functions. Dexamethasone/IL-27-mediated treatment of neutrophilic inflammation also failed in Treg-depleted or in Treg-specific Il27ra-/- mice, suggesting key roles of Tregs and of IL-27 signaling in Tregs. These preliminary results have led us to propose that Dex signaling induces Treg suppressive functions that limit eosinophilic inflammatory responses whereas control of neutrophilic inflammatory responses by Dex requires additional signals conferred by IL-27 to the Tregs. Three specific aims are proposed to test the hypothesis. Aim 1 is to test the hypothesis that that Dex downregulates eosinophilic airway inflammation by targeting Tregs. Aim 2 is to test the hypothesis that neutrophilic inflammation subverts Dex-induced Treg control of airway inflammation, resulting in Dex resistance. Aim 3 is to test the hypothesis that IL-27 signaling improves Dex responsiveness in Tregs to inhibit Dex-resistant neutrophilic inflammation. Completing the proposed studies will uncover the previously unknown mechanisms by which Tregs regulate both GC susceptible and GC resistant allergic airway inflammation, opening new opportunities to develop novel approaches to improve GC?s therapeutic efficacy and to overcome GC resistance by targeting Tregs.